Circumventing Acquired Resistance to Growth Factor Receptor Kinase Inhibitors

规避对生长因子受体激酶抑制剂的获得性耐药性

• 批准号: 7582308
• 负责人: Daniel A. Haber
• 金额: $ 36.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582308
• 关键词: Address; Affect; Antineoplastic Agents; Biological Assay; Cancer cell line; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Clinical effectiveness; Complement; Complex; Dependence; Development; Drug Delivery Systems; Drug resistance; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Erlotinib; Face; Family member; Gatekeeping; Gefitinib; Generations; Genetic; Genetic Markers; Gleevec; Growth Factor Receptors; Human; Imatinib; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Pathway interactions; Peptides; Pharmaceutical Preparations; Phase; Phosphotransferases; Phosphotyrosine; Protein Tyrosine Kinase; Proteomics; RNA Interference; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Tyrosine Kinase Inhibitor; Variant; abstracting; addiction; base; c-erbB-1 Proto-Oncogenes; cancer therapy; design; inhibitor/antagonist; insight; kinase inhibitor; mutant; novel; novel strategies; prototype; public health relevance; receptor; reconstitution; research study; resistance mechanism; response; small hairpin RNA; success; tumor

DESCRIPTION (provided by applicant): The success of molecularly targeted cancer therapy using tyrosine kinase inhibitors (TKIs) faces a number of difficult challenges. Foremost among these is the ability to identify subsets of different cancers that are uniquely sensitive to targeted agents, often identified by the presence of genetic markers implying "dependence" or "addiction" to the targeted pathway. Equally important to the longterm success of these therapies is understanding and circumventing acquired drug resistance, which is a key limitation to their clinical effectiveness. Acquired resistance to drugs targeting growth factor receptors differs from resistance to genotoxic cancer chemotherapy, and may include both specific mutations in targeted receptors, as well as more complex functional alterations in signaling networks. Here we will use non-small cell lung cancer (NSCLC) cell line models that appear to faithfully recapitulate key signaling dependence of cancers with activating mutations in the Epidermal Growth Factor Receptor (EGFR) gene, identifying a subset of lung cancers with extreme sensitivity to EGFR TKIs. We outline three aims that address the acquisition of resistance in tumors that were previously sensitive to these agents: in Aim 1, we will generate cell line models for acquired resistance to "second generation" irreversible inhibitors of EGFR, and use genetic, signaling and functional analyses to dissect the underlying mechanisms. In Aim 2, we will use a high throughput shRNA screen of tyrosine kinases to identify candidate targets whose suppression may circumvent resistance to EGFR inhibitors. In Aim 3, we will use lentiviral knockdown/reconstitution experiments to quantitate oncogene dependence of drug resistant cells, both on the initiating EGFR mutation and on associated signaling pathways that contribute to acquired drug resistance. Together, these aims will provide important insight into critical mechanisms that underlie the acquisition of resistance to novel inhibitors targeting growth factor receptors in human cancer. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms by which cancers that are sensitive to the new classes of targeted cancer therapies become resistant to these is critical to their eventual clinical success. Our approach is designed to dissect the molecular basis of resistance to these cancer drugs.

描述（由申请人提供）：使用酪氨酸激酶抑制剂（TKI）进行分子靶向癌症治疗的成功面临着许多困难的挑战。其中最重要的是能够识别对靶向药物独特敏感的不同癌症子集，通常通过暗示对靶向途径“依赖性”或“成瘾”的遗传标记的存在来识别。对于这些疗法的长期成功同样重要的是了解和规避获得性耐药性，这是其临床有效性的关键限制。对针对生长因子受体的药物的获得性耐药性与对基因毒性癌症化疗的耐药性不同，可能包括目标受体的特定突变，以及信号网络中更复杂的功能改变。在这里，我们将使用非小细胞肺癌 (NSCLC) 细胞系模型，这些模型似乎忠实地重现了癌症的关键信号依赖性，并激活了表皮生长因子受体 (EGFR) 基因中的突变，从而识别出对肺癌极其敏感的肺癌子集。 EGFR TKI。我们概述了三个目标，解决以前对这些药物敏感的肿瘤获得耐药性的问题：在目标 1 中，我们将生成对“第二代”不可逆 EGFR 抑制剂获得性耐药的细胞系模型，并使用遗传、信号传导和功能分析以剖析潜在机制。在目标 2 中，我们将使用酪氨酸激酶的高通量 shRNA 筛选来识别候选靶点，其抑制可能会规避对 EGFR 抑制剂的耐药性。在目标 3 中，我们将使用慢病毒敲低/重建实验来定量耐药细胞的癌基因依赖性，包括对起始 EGFR 突变和有助于获得性耐药的相关信号通路的依赖性。总之，这些目标将为人类癌症中针对生长因子受体的新型抑制剂获得耐药性的关键机制提供重要的见解。 公共卫生相关性：了解对新型靶向癌症疗法敏感的癌症产生耐药性的机制对于其最终的临床成功至关重要。我们的方法旨在剖析这些抗癌药物耐药性的分子基础。